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10/7/2015

ClusterHeadache:Background,Pathophysiology,Etiology

ClusterHeadache
Author:MichelleBlanda,MDChiefEditor:TarakadSRamachandran,MBBS,FRCP,FRCPCmore...
Updated:Apr08,2014

Background
Clusterheadache(CH),alsoknownashistamineheadache,isaprimary
neurovascularprimaryheadachedisorder,thepathophysiologyandetiologyofwhich
arenotwellunderstood. [1]Asthenamesuggests,CHinvolvesagroupingof
headaches,usuallyoveraperiodofseveralweeks.Accordingtothediagnostic
criteriadevelopedbytheInternationalHeadacheSociety(IHS),CHhasthe
followingcharacteristics[2,3]:
Thepatientexperiencesattacksofsevereorverysevere,strictlyunilateral
pain(orbital,supraorbital,ortemporalpain)thatlast15180minutesand
occurfromonceeveryotherdayto8timesaday
Theattacksareassociatedwith1ormoreofthefollowing(allipsilateral):
conjunctivalinjection,lacrimation,nasalcongestion,rhinorrhea,foreheadand
facialsweating,miosis,ptosis,oreyelidedema
CHmaybeusefullyclassifiedinto2mainformsasfollows:
EpisodicCH,inwhichatleast2clusterphaseslasting7daysto1yearare
separatedbyaclusterfreeintervalof1monthorlonger
ChronicCH,inwhichtheclustersoccurmorethanonceayearwithout
remissionortheclusterfreeintervalisshorterthan1month

Pathophysiology
TheunderlyingpathophysiologyofCHisincompletelyunderstood. [4,5]The
periodicityoftheattackssuggeststheinvolvementofabiologicclockwithinthe
hypothalamus(whichcontrolscircadianrhythms),withcentraldisinhibitionofthe
nociceptiveandautonomicpathwaysspecifically,thetrigeminalnociceptive
pathways.Positronemissiontomography(PET)andvoxelbasedmorphometryhave
identifiedtheposteriorhypothalamicgraymatterasthekeyareaforthebasic
defectinCH. [1]Seetheimagesbelow.

Clusterheadache:Functionalimagingshowsactivationofspecificbrainareasduringpain.
CourtesyofWikipediaCommons.

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ClusterHeadache:Background,Pathophysiology,Etiology

Clusterheadache(CH):Voxelbasedmorphometry(VBM)structuralimagingshowsspecific
brainareaofCHpatients'(hypothalamus)beingdifferenttononCHpatients'brains.Courtesyof
WikipediaCommons.

Alteredhabituationpatternsandchangeshavebeenobservedwithinthetrigeminal
facialneuronalcircuitrysecondarytocentralsensitization,inadditiontodysfunction
oftheserotonergicraphenucleihypothalamicpathways(thoughthelatterisnotas
strikingasinmigraine).Functionalhypothalamicdysfunctionhasbeenconfirmedby
abnormalmetabolismbasedontheNacetylaspartateneuronalmarkerinmagnetic
resonancespectroscopy. [6]
SubstancePneuronscarrysensoryandmotorimpulsesinthemaxillaryand
ophthalmicdivisionsofthetrigeminalnerve.Theseconnectwiththesphenopalatine
ganglionandinteriorcarotidperivascularsympatheticplexus.Somatostatininhibits
substancePandreducesthedurationandintensityofCH.
VasculardilatationmayplayaroleinthepathogenesisofCH,butbloodflow
studiesareinconsistent.Extracranialbloodflow(hyperthermiaandincreased
temporalarterybloodflow)increases,butonlyaftertheonsetofpain.Vascular
changeisconsideredsecondarytoprimaryneuronaldischarge.
Althoughtheevidencesupportingacausativeroleforhistamineisinconsistent,
clusterheadachesmaybeprecipitatedwithsmallamountsofhistamine.
Antihistaminesdonotabortclusterheadaches.Increasednumbersofmastcells
havebeenfoundintheskinofpainfulareasofsomepatients,butthisfindingis
inconsistent.

Etiology
TheexactcauseofCHisunknown.Thedisorderissporadic,thoughrarecasesof
anautosomaldominantpatternwithinasinglefamilyhavebeenreported.
SeveralfactorshavebeenshowntoprovokeCHattacks.Subcutaneousinjectionof
histamineprovokesattacksin69%ofpatients.Stress,allergens,seasonalchanges,
ornitroglycerinmaytriggerattacksinsomepatients.Alcoholinducesattacksduring
aclusterbutnotduringremission.About80%ofCHpatientsareheavysmokers,
and50%haveahistoryofheavyethanoluse.
RiskfactorsforCHincludethefollowing:
Malesex
Ageolderthan30years
Smallamountsofvasodilators(eg,alcohol)
Previousheadtraumaorsurgery(occasionally)

Epidemiology
TheexactprevalenceofCHintheUnitedStatesisunknownKudrowestimatedit
tobe0.4%inmenand0.08%inwomen. [7]Comparedwithclassicmigraine,CHis
relativelyuncommon,withanincidenceequivalenttoonly29%ofthatofmigraine.
Prevalenceinmalesis0.41%.Inanextensivestudyof100,000inhabitantsofthe
republicofSanMarino,theprevalencewas0.07%.TheincidenceofCHinthe
UnitedKingdomisequivalenttothatofmultiplesclerosis.

Age,sex,andracerelateddemographics
CHusuallybeginsinmiddleadultlife(eg,inthe30s)however,ithasbeenreported
inpatientsasyoungas1yearandasoldas79years.
CHismorecommoninmalesthaninfemalesthemaletofemaleratiowas6:1in
the1960sbutisnowcloserto2:1.Presentationsinfemalesmaydifferfromthose
inmales,accordingtodatafromtheUnitedStatesClusterHeadacheSurvey. [8]For
example,womentendtodevelopCHatanearlierageandarealsomorelikelyto
exhibitasecondpeakofCHincidenceaftertheageof50.
Racialandethnicdifferenceshavenotbeenwellstudied,butCHmaybeslightly
moreprevalentinAfricanAmericansandmaybeunderdiagnosedinblackwomen.

Prognosis
Generally,CHisalifelongproblem.Potentialoutcomesincludethefollowing:

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ClusterHeadache:Background,Pathophysiology,Etiology

Recurrentattacks
Prolongedremissions
Possibilityoftransformationofanepisodicclustertoachronicclusterand
viceversa
About80%ofpatientswithepisodicCHmaintaintheepisodicformofthedisorder.
In413%,episodicCHeventuallytransformsintochronicCH.Intermediate(mixed)
formsmayalsodevelop.Prolonged,spontaneousremissionsoccurinasmanyas
12%ofpatients,particularlyinthosewithepisodicCH.ChronicCHismore
relentlessandmaypersistinthisforminasmanyas55%ofcases.Lessfrequently,
chronicCHmayremitintoanepisodicform.
NoreportedmortalityisdirectlyassociatedwithCH.However,patientswithCHare
atincreasedriskforselfinjuryduringattacks,suicideattempts,alcoholuse(and
otherformsofsubstanceabuse),cigarettesmoking,andpepticulcerdisease.
Suicideshavebeenreportedincaseswhereattacksarefrequentandsevere.The
intensityoftheattacksoftenleadsCHpatientstomisstimefromactivitiessuchas
workorschool.Medicationsusedmayhavesideeffects,includingtheunmaskingof
coronaryarterydisease.
PharmacologicinterventionmayplayapartinthetransformationofchronicCHinto
theepisodicformotherwise,itdoesnotinfluenceoutcome.Lateonsetofthe
disorder,malesex,andpreviousepisodicCHallpredictalessfavorablecourse.

PatientEducation
PatientsshouldbeeducatedregardingtheneedtoavoidknownprecipitantsofCH.
Inaddition,theyshouldbeinstructedtoavoidhighaltitudes.
Forpatienteducationresources,seetheHeadacheCenter,aswellasCausesand
TreatmentsofMigraineandRelatedHeadaches,ClusterHeadache,Alternativeand
ComplementaryApproachestoMigraineandClusterHeadaches,ClusterHeadache
FAQs,andUnderstandingMigraineandClusterHeadacheMedications.
ClinicalPresentation

ContributorInformationandDisclosures
Author
MichelleBlanda,MDChairEmeritus,DepartmentofEmergencyMedicine,SummaHealthSystemAkron
City/StThomasHospitalProfessorofEmergencyMedicine,NortheasternOhioUniversitiesCollegeofMedicine
MichelleBlanda,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofEmergency
Physicians,SocietyforAcademicEmergencyMedicine
Disclosure:Nothingtodisclose.
Coauthor(s)
RimaMDafer,MD,MPH,FAHAAssociateProfessor,DepartmentofNeurologyandNeurologicalSurgery,
LoyolaUniversity,ChicagoStritchSchoolofMedicine
RimaMDafer,MD,MPH,FAHAisamemberofthefollowingmedicalsocieties:AmericanAcademyof
Neurology,AmericanHeartAssociation,AmericanHeadacheSociety
Disclosure:Nothingtodisclose.
ChiefEditor
TarakadSRamachandran,MBBS,FRCP,FRCPCProfessorEmeritusofNeurologyandPsychiatry,Clinical
ProfessorofMedicine,ClinicalProfessorofFamilyMedicine,ClinicalProfessorofNeurosurgery,StateUniversity
ofNewYorkUpstateMedicalUniversityNeuroscienceDirector,DepartmentofNeurology,CrouseIrving
MemorialHospital
TarakadSRamachandran,MBBS,FRCP,FRCPCisamemberofthefollowingmedicalsocieties:American
CollegeofInternationalPhysicians,AmericanHeartAssociation,AmericanStrokeAssociation,American
AcademyofNeurology,AmericanAcademyofPainMedicine,AmericanCollegeofForensicExaminersInstitute,
NationalAssociationofManagedCarePhysicians,AmericanCollegeofPhysicians,RoyalCollegeofPhysicians,
RoyalCollegeofPhysiciansandSurgeonsofCanada,RoyalCollegeofSurgeonsofEngland,RoyalSocietyof
Medicine
Disclosure:Nothingtodisclose.
Acknowledgements
JosephCarcioneJr,DO,MBAConsultantinNeurologyandMedicalAcupuncture,MedicalManagementand
OrganizationalConsulting,CentralWestchesterNeuromuscularCare,PCMedicalDirector,OxfordHealthPlans
JosephCarcioneJr,DO,MBAisamemberofthefollowingmedicalsocieties:AmericanAcademyofNeurology
Disclosure:Nothingtodisclose.
StevenCDronen,MD,FAAEMChair,DepartmentofEmergencyMedicine,LeConteMedicalCenter
StevenCDronen,MD,FAAEMisamemberofthefollowingmedicalsocieties:AmericanAcademyof
EmergencyMedicineandSocietyforAcademicEmergencyMedicine
Disclosure:Nothingtodisclose.
RagasriKumar,DOResidentPhysician,DepartmentofNeurology,LoyolaUniversityMedicalCenter
Disclosure:Nothingtodisclose.
EdwardAMichelson,MDAssociateProfessor,ProgramDirector,DepartmentofEmergencyMedicine,
UniversityHospitalHealthSystemsinCleveland
EdwardAMichelson,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofEmergency
Physicians,NationalAssociationofEMSPhysicians,andSocietyforAcademicEmergencyMedicine
Disclosure:Nothingtodisclose.

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LoriKSargeant,MDConsultingStaff,SummaEmergencyAssociates,Inc
LoriKSargeant,MDisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,AmericanCollegeof
EmergencyPhysicians,andOhioStateMedicalAssociation
Disclosure:Nothingtodisclose.
FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenterCollege
ofPharmacyEditorinChief,MedscapeDrugReference
Disclosure:MedscapeSalaryEmployment

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